Adiposity induces lethal cytokine storm after systemic administration of stimulatory immunotherapy regimens in aged mice

Annie Mirsoian, Myriam N. Bouchlaka, Gail D. Sckisel, Mingyi Chen, Chien Chun Steven Pai, Emanuel Maverakis, Richard G. Spencer, Kenneth W. Fishbein, Sana Siddiqui, Arta M. Monjazeb, Bronwen Martin, Stuart Maudsley, Charles Hesdorffer, Luigi Ferrucci, Dan L. Longo, Bruce R. Blazar, Robert H. Wiltrout, Dennis D. Taub, William J. Murphy

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Abstract

Aging is a contributing factor in cancer occurrence. We recently demonstrated that systemic immunotherapy (IT) administration in aged, but not young, mice resulted in induction of rapid and lethal cytokine storm. We found that aging was accompanied by increases in visceral fat similar to that seen in young obese (ob/ob or diet-induced obese [DIO]) mice. Yet, the effects of aging and obesity on inflammatory responses to immunotherapeutics are not well defined. We determine the effects of adiposity on systemic IT tolerance in aged compared with young obese mice. Both young ob/ob- and DIO-generated proinflammatory cytokine levels and organ pathologies are comparable to those in aged ad libitum mice after IT, culminating in lethality. Young obese mice exhibited greater ratios of M1/M2 macrophages within the peritoneal and visceral adipose tissues and higher percentages of TNF+ macrophages in response to αCD40/IL-2 as compared with young lean mice. Macrophage depletion or TNF blockade in conjunction with αCD40/IL-2 prevented cytokine storms in young obese mice and protected from lethality. Calorie-restricted aged mice contain less visceral fat and displayed reduced cytokine levels, protection from organ pathology, and protection from lethality upon αCD40/IL-2 administration. Our data demonstrate that adiposity is a critical factor in the age-associated pathological responses to systemic anti-cancer IT.

Original languageEnglish (US)
Pages (from-to)2373-2383
Number of pages11
JournalJournal of Experimental Medicine
Volume211
Issue number12
DOIs
StatePublished - Jan 1 2014

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Obese Mice
Adiposity
Immunotherapy
Intra-Abdominal Fat
Cytokines
Interleukin-2
Macrophages
Pathology
Diet
Age Factors
Peritoneal Macrophages
Neoplasms
Obesity

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Adiposity induces lethal cytokine storm after systemic administration of stimulatory immunotherapy regimens in aged mice. / Mirsoian, Annie; Bouchlaka, Myriam N.; Sckisel, Gail D.; Chen, Mingyi; Pai, Chien Chun Steven; Maverakis, Emanuel; Spencer, Richard G.; Fishbein, Kenneth W.; Siddiqui, Sana; Monjazeb, Arta M.; Martin, Bronwen; Maudsley, Stuart; Hesdorffer, Charles; Ferrucci, Luigi; Longo, Dan L.; Blazar, Bruce R.; Wiltrout, Robert H.; Taub, Dennis D.; Murphy, William J.

In: Journal of Experimental Medicine, Vol. 211, No. 12, 01.01.2014, p. 2373-2383.

Research output: Contribution to journalArticle

Mirsoian, A, Bouchlaka, MN, Sckisel, GD, Chen, M, Pai, CCS, Maverakis, E, Spencer, RG, Fishbein, KW, Siddiqui, S, Monjazeb, AM, Martin, B, Maudsley, S, Hesdorffer, C, Ferrucci, L, Longo, DL, Blazar, BR, Wiltrout, RH, Taub, DD & Murphy, WJ 2014, 'Adiposity induces lethal cytokine storm after systemic administration of stimulatory immunotherapy regimens in aged mice', Journal of Experimental Medicine, vol. 211, no. 12, pp. 2373-2383. https://doi.org/10.1084/jem.20140116
Mirsoian, Annie ; Bouchlaka, Myriam N. ; Sckisel, Gail D. ; Chen, Mingyi ; Pai, Chien Chun Steven ; Maverakis, Emanuel ; Spencer, Richard G. ; Fishbein, Kenneth W. ; Siddiqui, Sana ; Monjazeb, Arta M. ; Martin, Bronwen ; Maudsley, Stuart ; Hesdorffer, Charles ; Ferrucci, Luigi ; Longo, Dan L. ; Blazar, Bruce R. ; Wiltrout, Robert H. ; Taub, Dennis D. ; Murphy, William J. / Adiposity induces lethal cytokine storm after systemic administration of stimulatory immunotherapy regimens in aged mice. In: Journal of Experimental Medicine. 2014 ; Vol. 211, No. 12. pp. 2373-2383.
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AU - Pai, Chien Chun Steven

AU - Maverakis, Emanuel

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AU - Siddiqui, Sana

AU - Monjazeb, Arta M.

AU - Martin, Bronwen

AU - Maudsley, Stuart

AU - Hesdorffer, Charles

AU - Ferrucci, Luigi

AU - Longo, Dan L.

AU - Blazar, Bruce R.

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AU - Murphy, William J.

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